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WO1995035292A1 - Agent antiviral renfermant, a titre d'ingredient actif, un derive de benzodithiine - Google Patents

Agent antiviral renfermant, a titre d'ingredient actif, un derive de benzodithiine Download PDF

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Publication number
WO1995035292A1
WO1995035292A1 PCT/JP1995/001107 JP9501107W WO9535292A1 WO 1995035292 A1 WO1995035292 A1 WO 1995035292A1 JP 9501107 W JP9501107 W JP 9501107W WO 9535292 A1 WO9535292 A1 WO 9535292A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
dihydro
benzodithiin
substituent
compound
Prior art date
Application number
PCT/JP1995/001107
Other languages
English (en)
Japanese (ja)
Inventor
Tsuyosi Kajiyashiki
Ryu Sato
Tomoyuki Yokota
Kenji Sudo
Wataru Watanabe
Shiro Shigeta
Original Assignee
Rational Drug Design Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rational Drug Design Laboratories filed Critical Rational Drug Design Laboratories
Priority to AU25766/95A priority Critical patent/AU2576695A/en
Priority to US08/750,730 priority patent/US5698580A/en
Priority to EP95920263A priority patent/EP0770609A4/fr
Publication of WO1995035292A1 publication Critical patent/WO1995035292A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention provides an antiviral agent containing a 1,4-dihydro-2,3-benzodithiin derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and 1,4-dihydro-2 which is an active ingredient of the antiviral agent.
  • 3 Related to benzodithiin derivatives. More specifically, for the prophylactic or therapeutic treatment of viral diseases represented by respiratory diseases such as upper respiratory inflammation, lower respiratory inflammation, bronchitis, capillary bronchitis, and craves involving the RS virus (Respiratory syncytial virus). It relates to antiviral agents that are effective in treatment.
  • drugs used to treat viral diseases include acyclovir (guanine derivative), ganciclovir (guanine derivative), idoxperidine (2'-dexoxy-5-odouridine), and vidarabine (adenine derivative) as anti-herbal agents.
  • acyclovir guanine derivative
  • ganciclovir guanine derivative
  • idoxperidine 2'-dexoxy-5-odouridine
  • vidarabine adenine derivative
  • anti-herbal agents such as are known, also Aman evening Gin (1-amino-over tricyclo [3. 3.1. 1 3 '7] decane) and the like are known as anti-influenza agents.
  • ribavirin a nucleic acid analog, is only used as an antiviral agent against RS virus that causes severe respiratory illness in infants.
  • ribavirin is effective against RS virus, it should be used orally due to its high toxicity. It is only used for topical administration by inhalation. Ribavirin has also been shown to be teratogenic, carcinogenic, and mutagenic, and has been pointed out as having difficulty in clinical use. Therefore, at present, antiviral agents that have a clinically sufficient therapeutic effect and have low toxicity and side effects are desired.
  • an object of the present invention is to provide an antiviral agent having excellent antiviral activity and having less toxicity and side effects.
  • WO 95/35292 “Disclosure of invention_PCT / JP95 / 01107” That is, the present invention is as follows.
  • R 1 , R 2 , R 3 and R 4 each have a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, and a substituent
  • 1,4 dihydro-2,3-benzodithiin derivative (hereinafter sometimes abbreviated as 1,4 dihydro-2,3-benzodithiin derivative (I)) or a pharmacologically acceptable salt thereof
  • An anti-viral agent containing as an active ingredient (hereinafter sometimes abbreviated as 1,4 dihydro-2,3-benzodithiin derivative (I)) or a pharmacologically acceptable salt thereof
  • R 8 ′, R 9 , and R 1 (1 and R 11 each represent a lower alkyl group or a halogen atom which may have a substituent.
  • a pharmaceutical composition for treating a viral disease comprising a 3-benzodithiin derivative or a pharmacologically acceptable salt thereof.
  • Use of salt
  • the lower alkyl group of the lower alkyl group which may have a substituent represented by R 11 may be linear or branched.
  • the lower alkyl group include: , A methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group and a pentyl group.
  • These groups include a cycloalkyl group which may have a substituent; a heterocyclic group which may have a substituent; methylamino A lower alkylamino group such as a dimethylamino group, an isopropylamino group, or a t-butylamino group; a lower alkoxyl group such as a methoxy group, an isobromoboxyl group or a t-butoxy group; a hydroxyl group; a carboxyl group: a methoxycarbonyl group; An alkoxy group such as a propoxycarbonyl group and a t-butoxydicarbonyl group; and a group such as a cyano group may be present as a substituent.
  • examples of the cycloalkyl group of the cycloalkyl group which may have a substituent include a cyclohexyl group and a cyclopentyl group. These groups include low alkyl groups such as methyl group, isobutyryl group and pentyl group; low alkoxy groups such as hydroxyl group, isopropoxy group and t-butoxy group; fluorine atom, chlorine atom, and bromine.
  • Atoms such as atoms; low alkylamino groups such as methylamino, dimethylamino, isopropylamino and t-butylamino; low alkylalkyl groups such as methylthio, ethylthio, isopropylthio and neopentylthio.
  • arylthio groups such as phenylthio group, toluylthio group, and 11-naphthylthio group
  • acyl groups such as acetyl group, propionyl group and t-butoxy group
  • R 1, R 2, R 3 ,, R 5, R low pole Arukeniru group e and R 7 is a lower alkenyl group which may have a substituent represented by each linear at a be branched Examples of such a lower alkenyl group include a vinyl group, a propyl group, an isopropyl group and a prenyl group. These groups may have, as a substituent, the same group as used in the definition of the lower alkyl group which may have a substituent.
  • R 1 , R 2 , R s , R 5 , R ′ and R 7 each have a substituent represented by Examples of the aryl group which may be included include a phenyl group and a naphthyl group. These groups may have, as a substituent, the same groups as used in the definition of the cycloalkyl group which may have the above-mentioned S-substituent.
  • Examples of the alkoxycarbonyl group represented by R ′, R 2 , R 3 and R 4 include a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a t-butoxycarbonyl group and the like.
  • Examples of the low-handed alkylsulfinyl group represented by R ′, R 2 , R 3 and R 4 include a methylsulfinyl group and an isopropylsulfinyl group.
  • Examples of the arylsulfinyl group represented by R 1 , R 2 , R 3 and R * include a phenylsulfenyl group and a p-methoxyphenylsulfinyl group.
  • Examples of the arylsulfonyl group represented by each of R], R 2 , R 3 and include a phenylsulfonyl group and a p-methoxyx-xylsulfonyl group.
  • Examples of the acyl group represented by each of R 1 , R 2 , R 3 and R 4 include an acetyl group, a propionyl group, an isoptyryl group, and a Viva CJyl group.
  • Examples of the halogen atom represented by 11 include a fluorine atom, a chlorine atom, and a bromine atom.
  • salts of 1,4-dihydro-2,3-benzodithiin derivatives (I) include, for example, For example, acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid; and acid addition salts with organic acids such as fumaric acid, tartaric acid, succinic acid, citric acid, and methanesulfonic acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid
  • organic acids such as fumaric acid, tartaric acid, succinic acid, citric acid, and methanesulfonic acid.
  • the 1,4-dihydro-2,3-benzodithiin derivative (I) can be produced, for example, according to the following reaction step. Reaction process
  • X is a halogen atom represented by X, where c represents a halogen atom, a fluorine atom, chlorine atom, Gumoto Atoms, etc.
  • the dihalogenomethylbenzene derivative represented by the general formula (V) can also be obtained by reacting a dihydroxymethylbenzene derivative represented by the general formula (IV) with a halogenating agent such as phosphorus tribromide.
  • the resulting dihalogenomethylbenzene derivative represented by the general formula (V) is reacted with potassium thioacetate to obtain a dithioacetylbenzene derivative or the dihalogenomethylbenzene represented by the general formula (V).
  • Bisisothioperonium salts obtained by allowing thiourea to act on derivatives, such as sodium hydroxide
  • the dimercaptomethyl benzene derivative represented by the general formula (VI) can be obtained by reacting the above base.
  • the resulting dimercaptomethylbenzene derivative represented by the general formula ( VI) is reacted with an oxidizing agent such as hydrogen peroxide to obtain a 1,4-dihydro-12,3-benzodithiin derivative (I). be able to.
  • the 1,4-dihydro-2,3-benzodithiin derivative (I) is prepared by reacting bis (benzyltriethylammonium) tetrathiomolybdate with a dihalogenomethylbenzene derivative represented by the general formula (V). You can also get.
  • the purification of the thus obtained 1,4-dihydro-2,3-benzodithiine derivative (I) from the reaction mixture by the simple * method is generally the same as the method used for isolating and purifying an organic compound from the reaction mixture. It is performed in a similar manner.
  • the reaction mixture is poured into water, extracted with an organic solvent such as getyl ether or ethyl acetate, and the extract is washed with cold diluted hydrochloric acid, aqueous sodium bicarbonate, brine, etc., dried, and concentrated to obtain a crude product.
  • the crude product is purified by recrystallization, chromatography and the like, if necessary, to obtain a 1,4-dihydro-2,3-benzodithiin derivative (I).
  • the salt of the 1.4-dihydro-2,3-benzodithiin derivative (I) can be produced by a usual salt formation reaction.
  • dimethylbenzene derivative represented by the general formula (III) as a raw material is described in Journal of American Chemical Society, Vol. 70, pp. 2218-2219 (1948) or Vol. It can be produced by the method described on pages 4809-4810 (1950).
  • the dihydroxymethylbenzene derivative represented by the general formula (IV) is described in Synthetic Communications, Vol. 21, No. 8-9, pp. 1055-1069 (1991) or Japanese Patent Application Laid-Open No. 57-45126. It can be manufactured by the method described.
  • the 1,4-dihydro-2,3-benzodithiin derivative (I) or a salt thereof has valuable pharmacological properties, especially antiviral activity, and can be infected with or at risk of being infected by a virus.
  • other mammals e.g., C
  • C useful for the prophylactic or therapeutic treatment of mice, rats, rabbits, canines, cats, etc. c .
  • simple viruses of the family Herpesviridae may be used.
  • Herpes simplex virus type 1 Herpes simplex virus type 2, Human cytomegalovirus, Epstein-Barr virus , Varicella Zoster virus, Human herpes virus type 6; Human adenovirus of the adenoviridae family; Human adenovirus; Hepa-dnaviridae Hepatitis B virus; Human papilloma virus of the Papovaviridae family; and the like.
  • RNA viruses include Rubella virus of the Togaviridae family, Japanese encephalitis virus, Hepatitis C virus, and Paramyxovi-ridae family. Measles virus, para-influenza virus (Pa-rainfluenza virus), RS virus (Respiratory syncytial virus), mumps virus (Mumps virus): Influenza virus (Influenza of Orthomyxovirid-ae) virus); HIV (Human immunodeficiency virus) of the Retroviridae family (Retr-oviridae); Human T-lymphotropic virus: Rabies virus of the Rhabdoviridae family: Rabies virus: Picornavirus family ( Picornaviridae), human polio virus and hepatitis A virus (Hepatiti sA virus Ebola virus of the family Filoviridae, Marburg virus, and the like.
  • Measles virus para-influenza virus (Pa-rainfluenza virus), RS virus (Respiratory
  • the dosage of the 1,4-dihydro-2,3-benzodithiin derivative (I) or its salt varies depending on the disease, the severity of the patient, the tolerability of the drug, etc., but usually 10 to 1 per adult per day. It is an amount of 1000 mg, preferably 100-500 mg, which can be administered once or in divided doses. For administration, it can take any form suitable for the route of administration.
  • the 1,4-dihydro-2,3-benzodithiin derivative (I) or a salt thereof can be prepared for administration using any formulation method. Therefore, the antiviral agent of the present invention also includes a therapeutic drug composition containing the 1,4-dihydro-2,3-benzodithiin derivative (I) or a salt thereof.
  • a therapeutic drug composition containing the 1,4-dihydro-2,3-benzodithiin derivative (I) or a salt thereof.
  • Such a composition is prepared by conventional means using pharmaceutically acceptable excipients such as any required pharmaceutical carriers and excipients.
  • the preparation is desirably provided in a form suitable for absorption from the digestive tract.
  • Tablets and capsules for oral administration are in unit dosage form and include binders such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone; excipients such as lactose, corn starch, calcium phosphate, sorbit Glycine and the like; lubricants such as magnesium stearate, talc, polyethylene glycol, silica and the like; disintegrants such as potato starch and the like; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated by methods well known in the art.
  • Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, and the like.
  • Such liquid preparations may contain commonly used additives, for example, emollients, such as sorbitol syrup, methylcellulose, glucose Z-sugar syrup, gelatin, pi-xicetyl cellulose, carboxymethylcellulose, stearin Emulsifiers, such as lecithin, sorbitan monooleate, gum arabic; non-aqueous vehicles, such as almond oil, fractionated coconut oil, oily esters, propylene glycol, ethanol, etc .; preservatives Agents such as methyl P-hydroxybenzoate, propyl P-hydroxybenzoate, sorbic acid and the like.
  • Oral preparations should be used It can be a solid preparation, dissolved beforehand in water or another suitable vehicle.
  • composition When the composition is an injection, a 1,4 dihydro-2,3-benzodithiine derivative ( ⁇ ) or a salt thereof may be used as necessary to adjust a pH, a buffer, a stabilizer, a preservative, a preservative, and a solubilizer.
  • the preparation can be made into a subcutaneous, intramuscular or intravenous injection by a conventional method.
  • the composition When the composition is an aerosol, it can contain a propellant such as a fluorinated hydrocarbon.
  • Compound 1 was dissolved in acetone and the resulting solution was adsorbed on microcrystalline cellulose and dried. The dried product was mixed with corn starch, and a 20-fold powder of Compound 1 was prepared as a powder by a conventional method.
  • Talc 10 g Compound 100 was dissolved in acetone in a total amount of 100 g, and the resulting solution was adsorbed on microcrystalline cellulose and dried. The dried product was mixed with corn meal, lactose and carboxymethylcellulose calcium, and then an aqueous solution of polyvinylpyrrolidone was added as a binder, mixed, and then pressed into tablets of 10 Omg per tablet. One tablet contains 10 mg of compound 1.
  • a maintenance medium (Eagle MEM medium containing 2% bovine blood albumin) containing various concentrations of Compounds 1 to 13 or Ribavirin (control), and trypsin digestion in advance
  • a maintenance medium containing the HeLa cell suspension and the RS virus L 0 ng strain was added, and the mixture was centrifuged at low speed (700 xg) at room temperature for 5 minutes. After completion of the centrifugation, the cells were cultured in a carbon dioxide incubator at 35 for 5 days.
  • the MTT method (MTT : 3- (4,5-dimethylthiabul-12-yl) -1,2,5-diphenyltetrazolium bromide) was performed, and the percentage of viable cells was micro Colorimetry was performed using a plate reader.
  • the concentration of the compound that inhibited cell destruction by RS virus infection by 50% was shown as antiviral activity (EC 50 ).
  • a 50% cytotoxicity value (CC S0 ) of the compound was calculated by a test performed simultaneously with no inoculation of RS virus.
  • HeLa cells cultured in a monolayered state in a 24-well flat-bottomed multi-ray tray were inoculated with Long RS virus strain prepared in a maintenance medium (Eagle MEM medium containing 2 fetal calf serum), and 35'C Incubated for 1 hour in a gas incubator. After discarding the culture medium and washing with the maintenance medium, add the maintenance medium containing 0.6% methylcellulose containing various concentrations of compound 1 or ribavirin (control). The cells were cultured in a CO 2 incubator for 4 days. After completion of the culture, the cells were fixed with a 5% aqueous solution of formalin for 6 hours and washed with tap water. The cells were then stained with a 0.025% aqueous crystal violet solution.
  • a maintenance medium Eagle MEM medium containing 2 fetal calf serum
  • 35'C Incubated for 1 hour in a gas incubator. After discarding the culture medium and washing with the maintenance medium, add the maintenance medium containing 0.6% methylcellulose containing various concentrations of
  • the compound of the present invention has a convenient antiviral activity, and provides an antiviral agent which is effective for prophylactic or therapeutic treatment of a viral disease represented by RS virus.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Abstract

Agent antiviral renfermant, à titre d'ingrédient actif, un dérivé de 1,4-dihydro-2,3-benzodithiine répondant à la formule générale, ou son sel pharmacologiquement acceptable. Dans ladite formule, chacun des éléments R?1, R2, R3 et R4¿ représente hydrogène, alkyle inférieur éventuellement substitué, alcényle inférieur, aryle ou aralkyle, nitro, cyano, carboxy, alcoxycarboxy, alkylsulfinyle inférieur, arylsulfonyle, sulfamoyle, carbamoyle, acyle, hydrazino, halogène, -OR?5, -SR5 ou -NR6R7¿; et chacun des éléments R?5, R6 et R7¿ représente hydrogène, ou alkyle inférieur éventuellement substitué, alcényle inférieur ou aryle. Ce médicament présente une excellente activité antivirale et est donc efficace dans le traitement prophylactique ou thérapeutique des maladies dues aux virus représentés par le virus RS.
PCT/JP1995/001107 1994-06-21 1995-06-06 Agent antiviral renfermant, a titre d'ingredient actif, un derive de benzodithiine WO1995035292A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU25766/95A AU2576695A (en) 1994-06-21 1995-06-06 Antiviral agent containing benzodithiin derivative as active ingredient
US08/750,730 US5698580A (en) 1994-06-21 1995-06-06 Antiviral agent containing benzodithiin derivative as active ingredient
EP95920263A EP0770609A4 (fr) 1994-06-21 1995-06-06 Agent antiviral renfermant, a titre d'ingredient actif, un derive de benzodithiine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6138546A JPH083040A (ja) 1994-06-21 1994-06-21 ベンゾジチイン誘導体を有効成分とする抗ウイルス剤
JP6/138546 1994-06-21

Publications (1)

Publication Number Publication Date
WO1995035292A1 true WO1995035292A1 (fr) 1995-12-28

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PCT/JP1995/001107 WO1995035292A1 (fr) 1994-06-21 1995-06-06 Agent antiviral renfermant, a titre d'ingredient actif, un derive de benzodithiine

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US (1) US5698580A (fr)
EP (1) EP0770609A4 (fr)
JP (1) JPH083040A (fr)
AU (1) AU2576695A (fr)
CA (1) CA2193496A1 (fr)
WO (1) WO1995035292A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013155144A (ja) * 2012-01-31 2013-08-15 Sumitomo Seika Chem Co Ltd ジチオール化合物及び環状ジスルフィド化合物の製造方法
WO2014084898A1 (fr) * 2012-11-28 2014-06-05 Yansong Lu Nouveaux antioxydants de synthèse et leurs utilisations
KR102394038B1 (ko) * 2020-06-10 2022-05-06 원광대학교산학협력단 다이설파이드 화합물 및 이의 제조 방법

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3682963A (en) * 1970-07-06 1972-08-08 Kazimir Sestanj Dimethylbenzodithian-2-oxide

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1290913A (fr) * 1969-03-01 1972-09-27
ZA714360B (en) * 1970-07-06 1972-03-29 Ciba Geigy Ag New heterocyclic compounds and process for their manufacture
US4004018A (en) * 1974-06-20 1977-01-18 Uniroyal Inc. 2,3-Dihydro-1,4-dithiin 1,1,4,4-tetroxide antimicrobials

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3682963A (en) * 1970-07-06 1972-08-08 Kazimir Sestanj Dimethylbenzodithian-2-oxide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0770609A4 *

Also Published As

Publication number Publication date
JPH083040A (ja) 1996-01-09
AU2576695A (en) 1996-01-15
CA2193496A1 (fr) 1995-12-28
US5698580A (en) 1997-12-16
EP0770609A1 (fr) 1997-05-02
EP0770609A4 (fr) 1997-09-03

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